Ion (Organic Acid and Base) Transporters and Homeostasis: A Review with Reference to its Usefulness as Biomarkers
PRABIR K. MANDAL
Department of Biology, University of North Florida, Jackosnville, Florida, US
Organisms are continuously exposed to a great variety of xenobiotics via food and environment. Evolution has equipped the body with a plethora of protecting systems to defend itself against the potentially harmful effects of these compounds. One of the important defense mechanisms include the active extrusion of xenobiotics by commonly shared transport proteins, mainly located in kidney, liver and intestine. An attempt has been made to understand the structural and functional properties of organic anion transporters (OAT1, OAT2, OAT3) and organic cation transporters (OCTN1, OCTN2, OCT1, OCT2, OCT3). These transporters share a predicted 12- transmembrane domain (TMD) structure with a large extracellular loop between TMD1 and TMD2, carrying potential N-glycosylation sites. Conserved amino acid motifs revealed a relationship to the sugar transporter family within the major facilitator superfamily. Following heterologous expression, most OATs transported the model anion p-aminohippurate (PAH). OAT1, but not OAT2, exhibited PAH-alphaketoglutarate exchange. OCT1–3 transported the model cations tetraethylammonium (TEA), N(1)-methylnicotinamide, and 1-methyl-4-phenylpyridinium. OCTNs exhibited transport of TEA and/or preferably the zwitterionic carnitine. Substrate substitution as well as cis-inhibition experiments demonstrated polyspecificity of the OATs, OCTs, and OCTN1. On the basis of comparison of the structurally closely related OATs and OCTs, it may be possible to delineate the binding sites for organic anions and cations in future experiments. The purpose of this review is to highlight recent evidence that implicates that members of the OAT and OCT families as organic ion transport systems play a role in mediating the elimination of xenobiotics mainly by kidney and liver. The significant changes in the plasma electrolytes levels and Na+K+-ATPase activitycan serve as a valuable biomarker of pollutant exposure and effects.
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